Intercellular junctions mediate adhesion and communication between adjoining endothelial and epithelial cells. In the endothelium, junctional complexes comprise tight junctions, adherens junctions, and gap junctions. The expression and organization of these complexes depend on the type of vessels and the permeability requirements of perfused organs. Gap junctions are communication structures, which allow the passage of small molecular weight solutes between neighboring cells. Tight junctions serve the major functional purpose of providing a “barrier” and a “fence” within the membrane, by regulating paracellular permeability and maintaining cell polarity. Adherens junctions play an important role in contact inhibition of endothelial cell growth, paracellular permeability to circulating leukocytes and solutes. In addition, they are required for a correct organization of new vessels in angiogenesis (Physiol. Rev. 84(3), 869-901, 2004).
The mechanism by which epithelial and endothelial cells interact to form polarized tissue is of fundamental importance to multicellular organisms. Dysregulation of these barriers occurs in a variety of diseases, destroying the normal cellular environments and leading to organ failure.
Cerebral microvascular endothelial cells that form the blood-brain barrier (BBB) have tight junctions that are critical for maintaining brain homeostasis and low permeability.
The blood-brain barrier (BBB) is a specialized structure in the central nervous system (CNS), which participates in maintenance of a state of cerebrospinal fluid homeostasis by controlling the access of nutrients and toxic substances to the central nervous system (CNS).
The base membrane underlying the vasculature plays a critical role in maintaining the integrity of the BBB by providing structural support to the endothelial cell wall (Trends Neurosci. 1990; 13(5): 174-178). The BBB serves to protect the central nervous system (CNS) from invasive agents, such as inflammatory cells and bacteria, as well as from chemical agents.
A wide range of central nervous system (CNS) disorders associated with disruption of the BBB are known. Examples of the disorders include multiple sclerosis, experimental allergic encephalomyelitis, bacterial meningitis, ischemia, brain edema, Alzheimer's disease, acquired immune deficiency syndrome dementia complex (Helga E. DE Vries et al, Pharmacological Reviews, 49(2): 143-155, 1997), brain tumors (Davies D. C. et al., J Anat., 200 (6): 639-46, 2002), traumatic brain injury (Hartl R et. al., Acta Neurochir Suppl. 70: 240-242, 1997).
It has also been reported that, after focal stroke, there is a breakdown of the BBB with an associated increase in vascular permeability. Damage to the BBB often results in hemorrhage and edema, resulting in neuronal cell death (Biomedicine. 1974; 21:36-39, Stroke, 1998; 29(5): 1020-1030, Stroke, 2003; 34(3):806-812, J Neurotrauma. 1995; 12:833-842). Brain injury after focal stroke is primarily a result of the decrease in blood flow and of energy depletion due to occlusion of a cerebral blood vessel. The neuronal tissue becomes infracted as a result of these events, with contributions from excitotoxicity, enzyme activation, edema, and inflammation (Trends Pharmacol Sci. 1996; 17:227-233, Crit Care Med. 1988; 16:954-963).
Furthermore, systemic-derived inflammation has recently been shown to cause BBB tight junctional disruption and increased paracellular permeability. The BBB is capable of rapid modulation in response to physiological stimuli at the cytoskeletal level, which enables it to protect the brain parenchyma and maintain a homeostatic environment.
Research has shown that destruction of the BBB is associated with diseases of the CNS. However, there is little research on how the BBB might be protected.
Prostaglandins (hereinafter, referred to as PG(s)) are members of class of organic carboxylic acids, which are contained in tissues or organs of human or other mammals, and exhibit a wide range of physiological activity. PGs found in nature (primary PGs) generally have a prostanoic acid skeleton as shown in the formula (A):

On the other hand, some of synthetic analogues of primary PGs have modified skeletons. The primary PGs are classified into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structure of the five-membered ring moiety, and further classified into the following three types by the number and position of the unsaturated bond at the carbon chain moiety:
Subscript 1: 13,14-unsaturated-15-OH
Subscript 2: 5,6- and 13,14-diunsaturated-15-OH
Subscript 3: 5,6-, 13,14-, and 17,18-triunsaturated-15-OH.
Further, the PGFs are classified, according to the configuration of the hydroxyl group at the 9-position, into α type (the hydroxyl group is of an α-configuration) and β-type (the hydroxyl group is of a β-configuration).
PGE1 and PGE2 and PGE3 are known to have vasodilation, hypotension, gastric secretion decreasing, intestinal tract movement enhancement, uterine contraction, diuretic, bronchodilation and anti ulcer activities. PGF1α, PGF2α and PGF3α have been known to have hypertension, vasoconstriction, intestinal tract movement enhancement, uterine contraction, lutein body atrophy and bronchoconstriction activities.
Some 15-keto (i.e., having oxo at the 15-position instead of hydroxy)-PGs and 13,14-dihydro (i.e., having single bond between the 13 and 14-position)-15-keto-PGs are known as the substances naturally produced by the action of enzymes during the metabolism of primary PGs.
U.S. Pat. No. 5,290,811 to Ueno et al. describes that some 15-keto-PG compounds are useful for improvement of encephalic function. U.S. Pat. No. 5,290,811 indicates that when the bond between 13- and 14-positions is saturated, a keto-hemiacetal equilibrium may sometimes be formed by the formation of a hemiacetal between the hydroxy group at 11-position and the keto group at 15-position.
U.S. Pat. No. 5,317,032 to Ueno et al. describes prostaglandin compound cathartics, including the existence of bicyclic tautomers and U.S. Pat. No. 6,414,016 to Ueno describes the bicyclic tautomers as having pronounced activity as anti-constipation agents. The bicyclic tautomers, substituted by one or more halogen atoms can be employed in small doses for relieving constipation. At the C-16 position, especially, fluorine atoms can be employed in small doses for relieving constipation.